Sorge_2009_J.Pharmacol.Exp.Ther_330_633

Attempts to explain tobacco addiction have relied heavily on the assumption that each cigarette puff delivers a bolus of nicotine to the brain within seconds. However, nicotine transits from lungs to brain much more gradually than once thought. Nevertheless, animal self-administration studies continue to use rapid (e.g., <3-s) infusions, as well as high unit doses of nicotine (e.g., 15-30 microg/kg/infusion), each equivalent to one to two cigarettes. Here, we report that nicotine is self-administered across a range of infusion durations (3, 30, 60, and 120 s) in rats. Slow (30-s) infusions were preferred over fast (nominal 3-s) infusions and were self-administered across several reinforcement schedules, at doses as low as 3 microg/kg/infusion, equivalent to one to two puffs. A conventional "fast/high" self-administration procedure (3 s-30 microg/kg/infusion) was then compared with our new "slow/low" procedure (30 s-3 microg/kg/infusion) in rats trained on a progressive ratio schedule and acutely challenged with dopamine receptor antagonists. The D(1) antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) (6-25 microg/kg s.c.) reduced intake in both procedures and in rats self-administering cocaine (0.5 mg/kg/infusion). The D(2) antagonists spiperone (3-30 microg/kg s.c.) and sulpiride (5-20 mg/kg i.p.) increased intake of fast/high nicotine and cocaine, but markedly reduced intake of slow/low nicotine. In a final test, in which only infusion speed was varied, an acute spiperone challenge produced the same differential effect on nicotine self-administration. In conclusion, our new slow/low nicotine self-administration procedure, designed to better mimic smoking-associated nicotine intake, is pharmacologically distinct from the conventional fast delivery/high-dose procedure.